Vaccine therapy for ran protein diseases

Abstract

Aspects of the disclosure relate to compositions and methods for eliciting (or enhancing) anti-repeat-associated non-ATG (RAN) protein antibody expression or production in a subject. Administration of the compositions according to the methods of the present disclosure may in some embodiments result in decreased levels of RAN protein expression and/or aggregation. Such compositions and methods may therefore be useful for the treatment of diseases and disorders known to be associated with RAN proteins.

1 . A method for preventing or treating a disease or disorder associated with RAN proteins in a human subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a RAN protein vaccine, wherein administration of the RAN protein vaccine to the subject elicits production of one or more anti-RAN protein antibodies in the subject. 
     
     
         2 . The method of  claim 1 , wherein the disease or disorder associated with RAN proteins is amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), Fragile X Syndrome (FRAXA), Spinal Bulbar Muscular Atrophy (SBMA), Dentatorubropallidoluysian Atrophy (DRPLA), Spinocerebellar Ataxia 1 (SCA1), Spinocerebellar Ataxia 2 (SCA2), Spinocerebellar Ataxia 3 (SCA3), Spinocerebellar Ataxia 6 (SCA6), Spinocerebellar Ataxia 7 (SCA7), Spinocerebellar Ataxia 8 (SCA8), Spinocerebellar Ataxia 12 (SCA12), or Spinocerebellar Ataxia 17 (SCA17), amyotrophic lateral sclerosis (ALS), Spinocerebellar ataxia type 36 (SCA36), Spinocerebellar ataxia type 29 (SCA29), Spinocerebellar ataxia type 10 (SCA10), myotonic dystrophy type 1 (DM1), myotonic dystrophy type 2 (DM2), or Fuch's Corneal Dystrophy (CTG181). 
     
     
         3 . The method of  claim 2 , wherein the disease is:
 (a) ALS, and wherein the ALS is caused by one or more mutations in a C9Orf72 gene;   (b) HD, and wherein the HD is caused by one or more mutations in a Htt gene;   (c) AD, and wherein the AD is caused by one or more mutations in an LRP8, CASP8, and/or GREB1 gene;   (d) SCA36, and wherein the SCA36 is caused by one or more mutations in an SCA36 gene; or   (e) FTD, and wherein the FTD is caused by one or more mutations in a C9Orf72 gene.   
     
     
         4 . The method of  claim 1 , wherein cells of the subject translate one or more RAN proteins. 
     
     
         5 . The method of  claim 4 , wherein the RAN proteins being translated in the subject:
 (a) comprise one or more of the following: poly(CP), poly(GA), poly(GP), poly(PR), poly(GR), poly(PA), poly(A), poly(G), poly(S), poly(C), poly(Q), poly(GD), poly(GE), poly(GQ), poly(GT), poly(L), poly(LP), poly(LPAC (SEQ ID NO: 1)), poly(LS), poly(P), poly(QAGR (SEQ ID NO: 2)), poly(RE), poly(SP), poly(VP), poly(FP), or poly(GK); and/or   (b) are poly(GA), poly(GP), poly(GR), poly(PA), and/or poly(PR) RAN proteins expressed from a C9Orf72 expansion repeat of the subject.   
     
     
         6 . (canceled) 
     
     
         7 . The method of  claim 1 , wherein the RAN protein vaccine comprises one or more di-peptide repeat (DPR) peptide antigens. 
     
     
         8 . The method of  claim 7 , wherein each DPR peptide antigen comprises between 2 di-amino acid repeats and 150 di-amino acid repeats, optionally between:
 (a) 10 di-amino acid repeats and 25 di-amino acid repeats;   (b) 25 di-amino acid repeats and 50 di-amino acid repeats;   (c) 50 di-amino acid repeats and 100 di-amino acid repeats; or   (d) 100 di-amino acid repeats and 150 di-amino acid repeats.   
     
     
         9 . (canceled) 
     
     
         10 . The method of  claim 7 , wherein:
 (a) each of the one or more DPR peptide antigens comprises a (GA) x  (SEQ ID NO: 4), (GP) x  (SEQ ID NO: 5), (GR) x  (SEQ ID NO: 7), (PA) x  (SEQ ID NO: 8), (PR) x  (SEQ ID NO: 6), (CP) x  (SEQ ID NO:3), (A) x  (SEQ ID NO:9), (G) x  (SEQ ID NO:10), (S) x  (SEQ ID NO: 11), (C) x  (SEQ ID NO: 12), (Q) x  (SEQ ID NO: 13), (GD) x  (SEQ ID NO: 14), (GE) x  (SEQ ID NO: 15), (GQ) x  (SEQ ID NO:16), (GT) x  (SEQ ID NO:17), (L) x  (SEQ ID NO: 18), (LP) x  (SEQ ID NO: 19), (LPAC) X  (SEQ ID NO: 20), (LS) x  (SEQ ID NO: 21), (P) x  (SEQ ID NO: 22), (QAGR) X  (SEQ ID NO: 23), (RE) x  (SEQ ID NO: 24), (SP) x  (SEQ ID NO: 25), (VP) x  (SEQ ID NO: 26), (FP) x  (SEQ ID NO: 27), and/or (GK) x  (SEQ ID NO: 28) di-amino acid repeat, wherein x represents the number of repeat units of the antigen, and wherein x is 5, 10, 15, 20, 25, 30, 35, or 40;   (b) the DPR peptide antigen comprises (GA) 10 (SEQ ID NO: 4), (GA) 15  (SEQ ID NO: 4), (GA) 25  (SEQ ID NO: 4), (GR) 25  (SEQ ID NO: 7), (GP) 10  (SEQ ID NO: 5), (GP) 15  (SEQ ID NO: 5), (PR) 10 (SEQ ID NO: 6), or a combination thereof; or   (c) the DPR peptide antigen comprises [(GA) 15  (SEQ ID NO: 4)+(GR) 25  (SEQ ID NO: 7)+(PR) 10 (SEQ ID NO: 6)] or [(GA) 15  (SEQ ID NO: 4)+(GR) 25  (SEQ ID NO: 7)+(PR) 10 (SEQ ID NO: 6)+(GP) 10  (SEQ ID NO: 5)].   
     
     
         11 - 12 . (canceled) 
     
     
         13 . The method of  claim 7 , wherein the RAN protein vaccine further comprises one or more additional immunogens. 
     
     
         14 . The method of  claim 13 , wherein the one or more immunogens:
 (a) comprises keyhole limpet hemocyanin (KLH), Blue Carrier Immunogenic protein (CCH), bovine serum albumin (BSA), ovalbumin (OVA), diphtheria toxin, measles virus fusion protein (MVF), hepatitis B virus surface antigen (HB-sAg), tetanus toxin (TT), pertussis toxin (PT), a T-cell helper epitope, or a portion of any of the foregoing; and/or   (b) are linked to the DPR peptide antigen via one or more linking molecules.   
     
     
         15 . (canceled) 
     
     
         16 . The method of  claim 14 , wherein each of the one or more the linking molecules is selected from the group consisting of: an amino acid, Lys-, Gly-, and Lys-Lys-Lys. 
     
     
         17 - 18 . (canceled) 
     
     
         19 . The method of  claim 1 , wherein:
 (a) each of the one or more anti-RAN protein antibodies bind to a poly(CP), poly(GA), poly(GP), poly(PR), poly(GR), poly(PA), poly(A), poly(G), poly(S), poly(C), poly(Q), poly(GD), poly(GE), poly(GO), poly(GT), poly(L), poly(LP), poly(LPAC (SEQ ID NO: 1)), poly(LS), poly(P), poly(QAGR (SEQ ID NO: 2)), poly(RE), poly(SP), poly(VP), poly(FP), or poly(GK) di-amino acid repeat-containing RAN protein; and/or   (b) the anti-RAN protein antibodies are one or more of an anti-poly(CP), anti-poly(GA), anti-poly(GP), anti-poly(PR), anti-poly(GR), anti-poly(PA), anti-poly(A), anti-poly(G), anti-poly(S); anti-poly(C); anti-poly(Q); anti-poly(GD), anti-poly(GE), anti-poly(GQ), anti-poly(GT), anti-poly(L), anti-poly(LP), anti-poly(LPAC (SEQ ID NO: 1)), anti-poly(LS), anti-poly(P), anti-poly(QAGR (SEQ ID NO: 2)), anti-poly(RE), anti-poly(SP), anti-poly(VP), anti-poly(FP), and/or anti-poly(GK) antibody.   
     
     
         20 . The method of  claim 1 , wherein the subject is administered one or more additional doses of the RAN protein vaccine. 
     
     
         21 - 28 . (canceled) 
     
     
         29 . The method of  claim 1 , wherein the RAN protein vaccine comprises a B-cell epitope. 
     
     
         30 . The method of  claim 1 , wherein administration of the RAN protein vaccine reduces:
 (a) RAN protein expression in the subject, relative to the level of RAN protein expression present in the subject prior to administration; and/or   (b) RAN protein aggregation in the subject, relative to the level of RAN protein aggregation present in the subject prior to administration.   
     
     
         31 . The method of  claim 30 , wherein RAN protein expression and/or aggregation is reduced by 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% after administration of the RAN protein vaccine to the subject, relative to the level of RAN protein expression and/or aggregation present in the subject prior to administration. 
     
     
         32 - 33 . (canceled) 
     
     
         34 . The method of  claim 1 , wherein the RAN protein vaccine further comprises one or more adjuvants. 
     
     
         35 . The method of  claim 34 , wherein the one or more adjuvants comprise any one or more of: immune targeting adjuvants; immunomodulating adjuvants; incomplete Freund's adjuvant; aluminum phosphate; aluminum hydroxide; alum; Stimulon® QS-21; MPL®; interleukin-12; an oil formulation; a polymer; a micelle forming adjuvant; a saponin; an immunostimulating complex matrix (ISCOM matrix); a particle; DDA; DNA adjuvants; an encapsulating adjuvant; flagellin adjuvants; alhydrogel (Al(OH) 3 ); CpG1; CpG3 and/or adjuphos (AlPO 4 ). 
     
     
         36 . The method of  claim 1 , wherein the RAN protein vaccine is delivered to the subject in a composition comprising an exosome or in a composition comprising a nanoparticle, optionally a lipid nanoparticle. 
     
     
         37 - 38 . (canceled) 
     
     
         39 . The method of  claim 1 , wherein the RAN protein vaccine is an mRNA vaccine.